ABSTRACT Despite stabilizing rates of prescription opioid pain reliever (OPR) overdoses, opioid-related mortality continues to rise because of increasing rates of heroin use and poisoning. Between 2013 and 2014, national estimates of nonmedical use of OPRs in the previous year declined from 11.08 to 10.34 million individuals. In contrast, heroin use increased from 0.68 to 0.91 million individuals. Mortality from heroin increased 26% in the last year and more than 300% over the last five years. The shift in trend is more than ecologic, as 40% to 70% of individuals who use heroin report nonmedical use of an OPR prior to initiating heroin. This is a substantial departure from historical trajectories of heroin use. For the great majority of individuals who began heroin use in the 1960s, heroin was their first opioid. While the risk of transition to heroin from nonmedical use of OPRs is low, contributing and pre-disposing factors are poorly understood. The burden of OPR and heroin-related adverse events is particularly high for individuals in Medicaid programs because they are more likely to have substance use disorders and are disproportionately represented among overdose deaths. The state of Oregon recently developed a state Performance Improvement Project (PIP) to reduce the proportion of high-dose opioid prescriptions in its Medicaid program, which is now delivered through 16 regionally and health system defined Coordinated Care Organizations (CCOs). Because each CCO has flexibility to address the state's PIP, implementation across CCOs constitutes a natural experiment to study policy factors associated with change in OPR prescribing and heroin-related outcomes. In response to RFA-CE-16-003 (Research on Prescription Opioid Use, Opioid Prescribing, and Associated Heroin Risk; Priority #2), the objective of this studyis to evaluate the relationships between OPR prescribing, CCO opioid dose reduction initiatives on patterns of OPR utilization, heroin use, and opioid-related overdoses. The objective is achieved through three Specific Aims using a mixed methods approach. First, using a multisource linked database that includes prescription drug monitoring program (PDMP), Medicaid claims, vital statistics, and substance use treatment data from Oregon, relationships between OPR prescribing patterns and heroin-related outcomes will be tested. Second, using qualitative research methods, policies and procedures directed at improving the statewide high dose PIP by each CCO will be characterized. Finally, the effect of implementation of CCO PIP initiatives on high-risk OPR use and heroin-related outcomes will be evaluated. Findings from this study will contribute to our understanding of individual risk factors for transition to and overdose with heroin. Also, knowledge gained will assist local and national decision makers about policy levers to reduce the burden of OPR and heroin- related morbidity and mortality.